The invention relates to piperazine derivatives for inhibiting the replication of Human Immunodeficiency Virus.
Besides inducing a breakdown of the immune defences, reflected in infected patients by the occurrence of serious opportunist infectious diseases, infection with Human Immunodeficiency Virus (HIV), the major cell targets of which are the CD4+ T lymphocytes and the cells of the macrophage line, is responsible for a chronic inflammatory syndrome, most particularly in the central nervous system, which is manifested by neurological complications which are grouped together under the name HIV encephalopathy or subacute encephalitis. xe2x80x9cPlatelet Activating Factorxe2x80x9d (PAF), which has been identified as an early mediator of inflammation and allergy, appears to play an essential role in this inflammatory syndrome, not only on account of its role as an inflammation mediator, but also by means of its neurotoxicity.
The efficacy of a treatment in HIV infection is measured by the reduction of the viral load in the blood of the infected patients and by the restoration of the level of circulating CD4+ T lymphocytes. With respect to these criteria, two classes of anti-retroviral agents acting at two different steps in viral replication have been found to be effective to date and consequently form the basis of the current treatment of HIV infection. These are:
firstly, reverse transcriptase inhibitors which are directed toward inhibiting the activity of the viral enzyme which ensures the retrotranscription of the viral ribonucleic acid (RNA) into deoxyribonucleic acid (DNA), this being the form in which the virus passes into the nucleus of the infected cell and becomes incorporated into its cell genome. These reverse transcriptase inhibitors are represented by zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), lamivudine (3TC), stavudine (d4T) and nevirapine; and
secondly, protease inhibitors such as indinavir, ritonavir, saquinavir and nelfinavir, which act by inhibiting the activity of a viral enzyme involved in the process of maturation of the viral particles derived from the replicationxe2x80x94that is to say in the installation of their various internal proteins and enzymes xe2x80x94, this maturation process preceding the release of these particles toward other cells to be infected.
These anti-retroviral agents are usually used in combination: thus, triple therapy, which consists in combining two reverse transcriptase inhibitors and a protease inhibitor, is nowadays prescribed as the first line treatment, and quadruple-therapy protocols are currently under clinical evaluation.
Despite their value, the anti-retroviral agents currently available do not really solve the problem of HIV infection.
Specifically, firstly, they induce viral mutations which are responsible for the appearance of resistance to the treatment and, in the long term, for a phenomenon of therapeutic evasion resulting in a resumption of the infection. Furthermore, since the resistances induced are usually crossed between the various anti-retroviral agents, especially between the protease inhibitors, the therapeutic substitutions are very limited.
Secondly, some of these anti-retroviral agents are of limited diffusion in tissues. In particular, they are incapable of crossing the blood-brain barrier and consequently of reaching the central nervous system, which however constitutes a preferred target of the viral infection.
These anti-retroviral agents moreover have numerous side effects (anemia, leukopenia, nausea, vomiting, diarrhea, myalgia, headaches, peripheral neuropathy, skin rashes, fever, pancreatitis, liver toxicity, etc.), these effects being all the more pronounced when they are used in combination. Besides the possibility of these side effects resulting in patient non-compliance due to the inconvenience they cause to the patients, they may in certain cases impose stoppage of the treatment on account of the seriousness of their nature.
Finally, these anti-retroviral agents have the drawback of having limited activity on the virus itself and of being incapable of protecting or reestablishing the immune system of the infected patients.
The problem consequently arises, of providing compounds which, while being active on HIV and consequently suitable for effectively treating an infection with this virus, have broad diffusion in tissues and are especially capable of reaching the central nervous system, do not induce resistance and have no crossed resistance with the anti-retroviral agents currently used, make it possible not only to eliminate the virus but also to protect or even restore the immune system, and also have satisfactory tolerance which is compatible with optimal patient compliance.
1,4,-Bis(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-2-(N,N-methoxycarbonyl)-piperazine were disclosed in French patent application No. 89 13258 as anti-ischemic and anti-inflammatory agents.
Moreover, it was shown, in French patent applications No. 89 13259 and No. 90 04798 and in European patent application No. 0 368 670, that trisubstituted piperazine derivatives are capable of inhibiting in vitro the effects of PAF on blood platelet aggregation and, in this respect, can be used in the treatment of pathologies in which this mediator appears to be involved, and especially in the treatment of inflammatory syndromes and allergic syndromes (acute inflammations, gastrointestinal ulcerations, asthma, cardiac anaphylaxis, etc.).
The advantage of piperazine derivatives of this type as PAF antagonists was subsequently confirmed by the studies by Lamouri et al. (J. Med. Chem., 1993, 36, 8, 990-1000) and Heymans et al. (J. Lipid Mediators Cell Signalling, 1994, 10, 153-154; J. Lipid Mediators Cell Signalling, 1996, 15, 161-173) which were directed toward specifying the influence of the chemical structure of these compounds on their biological activity.
Now, continuing their studies on piperazine derivatives, the Inventors have discovered that, surprisingly, in addition to having anti-PAF activity, some of these derivatives are capable of very efficiently inhibiting HIV replication, and are thus suitable as a therapy of choice in the treatment of HIV infection since they make it possible not only to block the multiplication of this virus within the body and its ultimate elimination, but also to restore the immune functions by virtue of their inhibitory activity toward PAF.
One subject of the present invention is thus the use of a piperazine derivative corresponding to the general formula (I): 
in which:
A and B represent, independently of each other, a Cxe2x95x90O, Cxe2x95x90S or CR7R8 group in which R7 represents a hydrogen atom or a group chosen from methyl, cyano, cyanomethyl, CO2CH3 and (Cxe2x95x90O)CH3 groups, while R8 represents a hydrogen atom or a phenyl group;
R1, R2, R3, R4, R5 and R6 represent, independently of each other, a hydrogen atom, a hydroxyl group or a linear or branched C1-C5 alkoxy group;
X represents:
either a group chosen from Cxe2x95x90O, O(Cxe2x95x90O), O(Cxe2x95x90S), O(SO2), NH(Cxe2x95x90O), NH(Cxe2x95x90S), NH(SO2), S(Cxe2x95x90O) and S(Cxe2x95x90S) groups, in which case Y represents either a group NR9R10 or CR9R10 R11 in which R9, R10 and R11 represent, independently of each other, a hydrogen atom, a linear or branched C1 to C5 alkyl, C2 to C5 alkenyl or C2 to C5 alkynyl group, or a nitrogen heterocycle comprising from 5 to 10 atoms and optionally one or more heteroatoms chosen from nitrogen, oxygen and sulfur;
or an oxygen or sulfur atom or a group chosen from O(Cxe2x95x90O)O, NH(Cxe2x95x90O)O and S(Cxe2x95x90O)O groups, in which case Y represents a group CR9R10R11 in which R9, R10 and R11 have the same meaning as above;
or one of the pharmaceutically acceptable salts thereof, for the preparation of a medicinal product for inhibiting the replication of human immunodeficiency virus (HIV).
In the text hereinabove and hereinbelow:
the expression xe2x80x9clinear or branched C1 to C5 alkyl groupxe2x80x9d denotes any hydrocarbon-based group containing not more than 5 carbon atoms, such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or pentyl group;
the expression xe2x80x9clinear or branched C2 to C5 alkenyl groupxe2x80x9d denotes any hydrocarbon-based group containing from 2 to 5 carbon atoms and one or more carbon-carbon double bonds, such as a vinyl, allyl, butenyl, butadienyl or pentenyl group;
the expression xe2x80x9clinear or branched C2 to C5 alkynyl groupxe2x80x9d denotes any hydrocarbon-based group comprising from 2 to 5 carbon atoms and one or more carbon-carbon triple bonds, such as an ethynyl, propynyl, butynyl or pentynyl group;
the expression xe2x80x9clinear or branched C1 to C5 alkoxy groupxe2x80x9d denotes any group of formula OR in which R represents a saturated or unsaturated hydrocarbon-based chain containing not more than 5 carbon atoms, such a methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, allyloxy, butenyloxy, methylpropenyloxy, pentenyloxy, methylbutenyloxy or pentadienyloxy group, and
the expression xe2x80x9cnitrogen heterocycle containing from 5 to 10 atoms and optionally one or more other heteroatoms chosen from nitrogen, oxygen and sulfurxe2x80x9d denotes any saturated or unsaturated ring containing from 5 to 10 atoms, at least one of which is a nitrogen atom, and optionally containing one or more other atoms chosen from nitrogen, oxygen and sulfur, such as pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidyl or indolyl group.
In accordance with the invention, R1, R2 and R3 are preferably borne by the carbon atoms in positions 3xe2x80x2,4xe2x80x2 and 5xe2x80x2 of the phenyl nucleus linked to the group A, while R4, R5 and R6 are preferably borne by the carbon atoms in positions 3xe2x80x2,4xe2x80x2 and 5xe2x80x2 of the phenyl nucleus linked to the group B.
According to a first preferred embodiment of the invention, the piperazine derivative corresponds to the specific formula (I-a): 
in which A and B represent, independently of each other, a Cxe2x95x90O or Cxe2x95x90S group, while R1, R2, R3, R4, R5, R6, X and Y have the same meaning as in the general formula (I) defined above.
Advantageously, in the specific formula (I-a), R1, R2, R4 and R5 represent a methoxy group, R3 and R6 both represent a hydrogen atom or a methoxy group, X represents:
either an O(Cxe2x95x90O) or NH(Cxe2x95x90O) group, in which case Y represents a group NR9R10 or CR9R10R11 in which R9, R10 and R11 have the same meaning as in the general formula (I) above, or alternatively a nitrogen heterocycle containing from 5 to 10 atoms and optionally one or more other heteroatoms chosen from nitrogen, oxygen and sulfur;
or an NH(Cxe2x95x90O)O group, in which case Y represents a group CR9R10R11 in which R9, R10 and R11 have the same meaning as in the general formula (I) above.
The piperazine derivative corresponding to the specific formula (1-a) is preferably chosen from 1,4-bis(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine, 1,4-bis(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-2-(N,N-dipropylaminocarbonyloxymethyl)piperazine, 1,4-bis(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-2-(1xe2x80x2-piperidinocarbonyloxymethyl)piperazine, 1,4-bis(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-2-(1xe2x80x2-pyrrolidinocarbonyloxymethyl)piperazine, 1,4-bis(3xe2x80x2,4xe2x80x2-dimethoxybenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine, 1,4-bis(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-2-(isopropyloxycarbonylaminomethyl)piperazine, 1,4-bis(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-2-(tert-butylcarbonylaminomethyl)piperazine, 1-(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-4-(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxythiobenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine, 1,4-bis(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxythiobenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine and 1-(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxythiobenzoyl)-4-(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine.
In a particularly preferred manner, the piperazine derivative corresponding to the specific formula (I-a) is 1,4-bis(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine.
According to another preferred embodiment of the invention, the piperazine derivative corresponds to the specific formula (I-b): 
in which R8 represents a hydrogen atom or a phenyl group, while R4, R5, R6, X and Y have the same meaning as in the general formula (I) defined above.
Advantageously, in the specific formula (I-b), R4, R5 and R6 represent a methoxy group, X represents an O(Cxe2x95x90O) group, while Y represents a group NR9R10 in which R9 and R10 both represent a linear or branched C1 to C5 alkyl, C2 to C5 alkenyl or C2 to C5 alkynyl group, or alternatively a nitrogen heterocycle containing from 5 to 10 atoms and optionally one or more other heteroatoms chosen from nitrogen, oxygen and sulfur.
The piperazine derivative corresponding to the specific formula (I-b) is preferably chosen from 1-benzyl-4-(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine and 1-diphenylmethyl-4-(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine.
According to yet another preferred embodiment of the invention, the piperazine derivative corresponds to the specific formula (I-c): 
in which R8 represents a hydrogen atom or a phenyl group, while R1, R2, R3, X and Y have the same meaning as in the general formula (I) defined above.
Advantageously, in the specific formula (I-c), R1, R2 and R3 represent a methoxy group, X represents an O(Cxe2x95x90O) group, while Y represents a group NR9R10 in which R9 and R10 both represent a linear or branched C1 to C5 alkyl, C2 to C5 alkenyl or C2 to C5 alkynyl group, or a nitrogen heterocycle containing from 5 to 10 atoms and optionally one or more other heteroatoms chosen from nitrogen, oxygen and sulfur.
The piperazine derivative corresponding to the specific formula (I-c) is preferably 1-(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-4-benzyl-2-(N,N-diethylamino-carbonyloxymethyl)piperazine.
There are many advantages in using the piperazine derivatives of general formula (I) and the pharmaceutically acceptable salts thereof to prepare a medicinal product for inhibiting HIV replication. Specifically, besides being able to control the spread of the virus in infected patients and its ultimate elimination by virtue of their antiviral action, they are capable of inducing a reconstruction of the immune system of these patients by means of their inhibitory action on PAF activity. Moreover, although their mechanism of action on HIV replication has not yet been fully elucidated, these piperazine derivatives do not appear to act either on reverse transcriptase or on viral protease, and as such their use makes it possible to overcome problems of crossed resistance currently encountered by clinicians in the treatment of HIV infection. In addition, the piperazine derivatives that are useful in accordance with the invention show an absence of cytotoxicity, which argues in favor of a very satisfactory tolerance.
The piperazine derivatives of general formula (I) and the pharmaceutically acceptable salts thereof can be obtained by a process which comprises:
when the derivative which it is desired to prepare corresponds to the general formula (I) in which A and B are both a Cxe2x95x90O group and when the phenyl nuclei to which they are attached bear the same substituents:
a) the acylation of a compound corresponding to the general formula (II) below: 
in which X and Y have the same meaning as in the general formula (I) defined above, with a reagent of general formula (III) below: 
xe2x80x83in which Hal represents a halogen atom and preferably a chlorine atom, while Rxe2x80x2, Rxe2x80x3 and Rxe2x80x2xe2x80x3 represent, independently of each other, a hydrogen atom, a hydroxyl group or a linear or branched C1-C5 alkoxy group, followed, if so desired, by
b) the conversion of the compound obtained in step a) into a pharmaceutically acceptable salt thereof,
when the derivative which it is desired to prepare corresponds to the general formula (I) in which A and B are both a Cxe2x95x90O group and when the phenyl nuclei to which they are attached bear different substitutents:
a) the acylation of a compound corresponding to the general formula (II) as defined above, with a reagent of general formula (III-a) below, and then with a reagent of general formula (III-b) below: 
xe2x80x83in which Hal represents a halogen atom and preferably a chlorine atom, while R1, R2, R3, R4, R5 and R6 have the same meaning as in the general formula (I) defined above, followed, if so desired, by
b) the conversion of the compound obtained in step a) into a pharmaceutically acceptable salt thereof;
when the derivative which it is desired to prepare corresponds to the general formula (I) in which A and B are both a Cxe2x95x90S group and when the phenyl nuclei to which they are attached bear the same substitutents:
a) the acylation of a compound corresponding to the general formula (II) as defined above, with a reagent of general formula (III) as defined above,
b) the reaction of the compound obtained in step a) with a reagent capable of converting a carbonyl function into a thiocarbonyl function, such as, for example, Lawesson""s reagent, followed, if so desired, by
c) the conversion of the compound obtained in step b) into a pharmaceutically acceptable salt thereof;
when the derivative which it is desired to prepare corresponds to the general formula (I) in which one of the two groups A and B is a Cxe2x95x90O group, while the other is a Cxe2x95x90S group, and when the phenyl nuclei to which they are attached bear the same substituents:
a) the acylation of a compound corresponding to the general formula (II) as defined above, with a reagent of general formula (III) as defined above, after having optionally protected (for example by tritylation) the nitrogen atom in position 4 of the piperazine ring of the compound,
b) the reaction of the compound obtained in step a) with a reagent capable of converting a carbonyl function into a thiocarbonyl function,
c) the acylation of the compound obtained in step b) with a reagent of general formula (III) as defined above, after deprotection (for example by detritylation) of the nitrogen atom in position 4 of the piperazine ring, if this atom was protected, followed, if so desired, by
d) the conversion of the compound obtained in step c) into a pharmaceutically acceptable salt thereof;
when the derivative which it is desired to prepare corresponds to the general formula (I) in which A is a Cxe2x95x90O group, while B is a Cxe2x95x90S group, and when the phenyl nuclei to which they are attached bear different substituents:
a) the acylation of a compound corresponding to the general formula (II) as defined above, with a reagent of general formula (III-a) as defined above,
b) the reaction of the compound obtained in step a) with a reagent capable of converting a carbonyl function into a thiocarbonyl function,
c) the acylation of the compound obtained in step b) with a reagent of general formula (III-b) as defined above, followed, if so desired, by
d) the conversion of the compound obtained in step c) into a pharmaceutically acceptable salt thereof;
when the derivative which it is desired to prepare corresponds to the general formula (I) in which A is a Cxe2x95x90S group, while B is a Cxe2x95x90O group, and when the phenyl nuclei to which they are attached bear different substituents:
a) the acylation of a compound corresponding to the general formula (II) as defined above, with a reagent of general formula (III-b) as defined above, after having protected the nitrogen atom in position 4 of the piperazine ring of this compound,
b) the reaction of the compound obtained in step a) with a reagent capable of converting a carbonyl function into a thiocarbonyl function,
c) the acylation of the compound obtained in step b) with a reagent of general formula (III-b) as defined above, after deprotection of the nitrogen atom in position 4 of the piperazine ring, followed, if so desired, by
d) the conversion of the compound obtained in step c) into a pharmaceutically acceptable salt thereof;
when the derivative which it is desired to prepare corresponds to the general formula (I) in which A and B are both a group CR7R8 and when the phenyl nuclei to which they are attached bear the same substituents:
a) the acylation of a compound corresponding to the general formula (II) as defined above, with a reagent of general formula (IV) below: 
xe2x80x83in which Hal represents a halogen atom and, preferably a chlorine atom, R7 and R8 have the same meaning as in the general formula (I) defined above, while Rxe2x80x2, Rxe2x80x3 and Rxe2x80x2xe2x80x3 represent, independently of each other, a hydrogen atom, a hydroxyl group or a linear or branched C1 to C5 alkoxy group followed, if so desired, by
b) the conversion of the compound obtained in step a) into a pharmaceutically acceptable salt thereof;
when the derivative which it is desired to prepare corresponds to the general formula (I) in which A and B are both a group CR7R8 and when the phenyl nuclei to which they are attached bear different substituents:
a) the acylation of a compound corresponding to the general formula (II) as defined above with a reagent of general formula (IV-a) below, and then with a reagent of general formula (IV-b) below: 
xe2x80x83in which Hal represents a halogen atom and preferably a chlorine atom, while R1, R2, R3, R4, R5, R6, R7 and R8 have the same meaning as in the general formula (I) defined above;
b) the conversion of the compound obtained in step a) into a pharmaceutically acceptable salt thereof;
when the derivative which it is desired to prepare corresponds to the general formula (I) in which one of the two groups A and B is a Cxe2x95x90O group, while the other is a group CR7R8:
a) the acylation of a compound corresponding to the general formula (II) as defined above, with a reagent of general formula (III) as defined above, after having optionally protected the nitrogen atom in position 4 of the piperazine ring of this compound,
b) the acylation of the compound obtained in step a) with a reagent of general formula (IV) as defined above, after deprotection of the nitrogen atom in position 4 of the piperazine ring when this atom has been protected, followed, if so desired, by
c) the conversion of the compound obtained in step b) into a pharmaceutically acceptable salt thereof.
The compounds of general formula (II) in which X represents a O(Cxe2x95x90O) group may be prepared from 1,4-dibenzyl-2-hydroxymethylpiperazine (which may be obtained by the process disclosed by Jucker and Rissi in Helv. Chem. Acta, 1962, 45, 2383-2402) by acylating this compound with an aryl halocarbonate such as phenyl chlorocarbonate, followed by subjecting the resulting compound to a substitution reaction by the action of a reagent of formula Hxe2x80x94Y in which Y has the same meaning as in the general formula (II), and, finally, by subjecting the compound thus obtained to a hydrogenolysis, for example by means of palladium on active charcoal.
The compounds of general formula (II) in which X represents a O(Cxe2x95x90S) group may also be prepared from 1,4-dibenzyl-2-hydroxymethylpiperazine, but in this case said compound is subjected to an addition-elimination reaction, for example by the successive action of thiophosgene and of a reagent of formula Hxe2x80x94Y in which Y has the same meaning as in the general formula (II), followed by subjecting the resulting compound to a debenzylation, for example using 2,2,2-trichloroethyl chloroformate, and in the presence of zinc and acetic acid.
The compounds of general formula (II) in which X represents an O(SO2) group may also be obtained from 1,4-dibenzyl-2-hydroxymethylpiperazine by subjecting said compound to an addition-elimination reaction, for example by the successive action of sulfuryl chloride and a reagent of formula Hxe2x80x94Y in which Y has the same meaning as in the general formula (II), followed by subjecting the resulting compound to a debenzylation.
The compounds of general formula (II) in which X represents an NH(Cxe2x95x90O), NH(Cxe2x95x90S) or NH(Cxe2x95x90O)O group may be prepared from 1,4-dibenzyl-2-aminomethylpiperazine by reacting said compound with a reagent chosen from the reagents of formulae Hal(Cxe2x95x90O)Y, Hal(Cxe2x95x90S)Y and Hal(Cxe2x95x90O)Oxe2x80x94Y in which Hal represents a halogen atom, and preferably a chlorine atom, while Y has the same meaning as in the general formula (II), followed by subjecting the resulting compound to a hydrogenolysis, when X represents an NH(Cxe2x95x90O) or NH(Cxe2x95x90O)O group, and to a debenzylation, when X represents an NH(Cxe2x95x90S) group.
The compounds of general formula (II) in which X represents an NH(SO2) group may also be prepared from 1,4-dibenzyl-2-aminomethylpiperazine, but in this case said compound is subjected to an addition-elimination reaction, for example by the successive action of sulfuryl chloride and of a reagent of formula Hxe2x80x94Y in which Y has the same meaning as in the general formula (II), followed by a debenzylation.
1,4-Dibenzyl-2-aminomethylpiperazine may itself be obtained by reacting 2,3-dibromopropionitrile with N,Nxe2x80x2-dibenzylethylenediamine in the presence of triethylamine and benzene, so as to obtain 1,4-dibenzyl-2-cyanopiperazine, followed by subjecting this compound to a reduction reaction, for example by the action of lithium aluminum hydride.
The compounds of general formula (II) in which X represents an S(Cxe2x95x90O) group may be prepared from 1,4-dibenzyl-2-thiomethylpiperazine by acylating this compound with an aryl halocarbonate such as phenyl chlorocarbonate, followed by subjecting the resulting compound to a substitution reaction by the action of a reagent of formula Hxe2x80x94Y in which Y has the same meaning as in the general formula (II), and finally, by subjecting the compound thus obtained to a debenzylation.
Similarly, the compounds of general formula (II) in which X represents an S(Cxe2x95x90S) group may be prepared from 1,4-dibenzyl-2-thio-methylpiperazine by subjecting this compound to an addition-elimination reaction, for example by the successive action of thiophosgene and of a reagent of formula Hxe2x80x94Y in which Y has the same meaning as in the general formula (II), and by subjecting the compound thus obtained to a debenzylation
1,4-Dibenzyl-2-thiomethylpiperazine may itself be obtained from 1,4-dibenzyl-2-chloromethylpiperazine by subjecting this compound to a nucleophilic substitution reaction, for example by means of sodium or potassium thioacetate, followed by saponifying the resulting compound with a base such as sodium hydroxide.
The compounds of general formula (II) in which X represents an oxygen atom or a sulfur atom may themselves be prepared, respectively, from 1,4-dibenzyl-2-hydroxymethylpiperazine and 1,4-dibenzyl-2-thiomethylpiperazine, by subjecting these compounds to an etherification, for example by the action of a base, and then of a reagent of formula Hal-Y in which Hal represents a halogen atom and preferably a chlorine atom, while Y has the same meaning as in the general formula (II) followed by subjecting the compound thus obtained to a hydrogenolysis.
The compounds of general formula (II) in which X represent either an O(Cxe2x95x90O)O group or an S(Cxe2x95x90O)O group may be obtained from 1,4-dibenzyl-2-hydroxymethylpiperazine and 1,4-dibenzyl-2-thiomethylpiperazine, respectively, by subjecting them to an addition-elimination reaction, for example by the action of a reagent of formula Hal(Cxe2x95x90O)Oxe2x80x94Y in which Hal represents a halogen atom and preferably a chlorine atom, while Y has the same meaning as in the general formula (II), followed by subjecting the resulting compounds to a debenzylation.
The present invention encompasses, for use in preparing a medicinal product intended to inhibit HIV replication, both known piperazine derivatives and piperazine derivatives that are novel per se.
A subject of the present invention is thus also novel piperazine derivatives which correspond to the general formula (I) as defined above, with the condition, however, that, in this general formula (I):
when R1, R2 and R3 are saturated, linear or branched C1 to C4 alkoxy groups, and are borne by the carbon atoms located in positions 3xe2x80x2,4xe2x80x2 and 5xe2x80x2 of the phenyl nucleus linked to the group A, and when B is a Cxe2x95x90O group, Y is other than:
a linear or branched C1 to C4 alkyl, C2 to C4 alkenyl or C2 to C4 alkynyl group, when X represents an oxygen or sulfur atom; and
a linear or branched C1 to C4 alkyl, C2 to C4 alkenyl or C2 to C4 alkynyl group, or an amine which is unsubstituted or substituted with one or two linear or branched C1 to C4 alkyl, C2 to C4 alkenyl or C2 to C4 alkynyl groups, when X represents a Cxe2x95x90O or O(Cxe2x95x90O) group;
when R1, R2, R3, R4, R5 and R6 all represent a methoxy group and when R1, R2 and R3 are borne by the carbon atoms located in positions 3xe2x80x2,4xe2x80x2 and 5xe2x80x2 of the phenyl nucleus linked to the group A, while R4, R5 and R6 are borne by the carbon atoms located in positions 3xe2x80x2,4xe2x80x2 and 5xe2x80x2 of the phenyl nucleus linked to the group B, Y is other than:
a linear or branched C5 or C6 alkyl group, an amine substituted with a linear or branched C5 alkyl group, or an amine substituted with two linear C5 alkyl groups, when A and B both represent a Cxe2x95x90O group and X represents an O(Cxe2x95x90O) group; and
a group CH(CH2CH3)2, when A and B both represent a CH2 group and X represents an O(Cxe2x95x90O) group;
as well as the pharmaceutically acceptable salts thereof.
In accordance with the invention, in these novel piperazine derivatives, R1, R2 and R3 are preferably borne by the carbon atoms located in positions 3xe2x80x2,4xe2x80x2 and 5xe2x80x2 of the phenyl nucleus linked to the group A, while R4, R5 and R6 are preferably borne by the carbon atoms located in positions 3xe2x80x2,4xe2x80x2 and 5xe2x80x2 of the phenyl nucleus linked to the group B.
According to a first preferred embodiment of these novel piperazine derivatives, said derivatives correspond to the specific formula (I-a): 
in which A and B represent, independently of each other, a Cxe2x95x90O group or a Cxe2x95x90S group, while R1, R2, R3, R4, R5, R6, X and Y have the same meaning as in the general formula (I) defined above, with the condition, however, that:
when R1, R2 and R3 are saturated, linear or branched C1 to C4 alkoxy groups, and when B is a Cxe2x95x90O group, Y is other than:
a linear or branched C1 to C4 alkyl, C2 to C4 alkenyl or C2 to C4 alkynyl group, when X represents an oxygen or sulfur atom; and
a linear or branched C1 to C4 alkyl, C2 to C4 alkenyl or C2 to C4 alkynyl group, or an amine which is unsubstituted or substituted with one or two linear or branched C1 to C4 alkyl, C2 to C4 alkenyl or C2 to C4 alkynyl groups, when X represents a Cxe2x95x90O or O(Cxe2x95x90O) group;
when R1, R2, R3, R4, R5 and R6 all represent a methoxy group, Y is other than a linear or branched C5 or C6 alkyl group, an amine substituted with a linear or branched C5 alkyl group, or an amine substituted with two linear C5 alkyl groups, when X represents an O(Cxe2x95x90O) group.
Among the novel piperazine derivatives of specific formula (I-a), the ones that are particularly preferred are those in which R1, R2, R4 and R5 represent a methoxy group, R3 and R6 both represent a hydrogen atom or a methoxy group, and X represents:
either an O(Cxe2x95x90O) group, in which case Y represents a nitrogen heterocycle containing from 5 to 10 atoms and optionally one or more other heteroatoms chosen from nitrogen, oxygen and sulfur, or alternatively, when R3 and R6 represent a hydrogen atom, a group NR9R10 in which R9 and R10 both represent a linear or branched C1 to C5 alkyl, C2 to C5 alkenyl or C2 to C5 alkynyl group;
or an NH(Cxe2x95x90O) group, in which case Y represents either a group NR9R10 or CR9R10R11in which R9, R10 and R11 represent, independently of each other, a hydrogen atom or a linear or branched C1 to C5 alkyl, C2 to C5 alkenyl or C2 to C5 alkynyl group, or a nitrogen heterocycle containing from 5 to 10 atoms and optionally one or more other heteroatoms chosen from nitrogen, oxygen and sulfur;
or an NH(Cxe2x95x90O)O group, in which case Y represents a group CR9R10R11 in which R9, R10 and R11 represent, independently of each other, a hydrogen atom or a linear or branched C1 to C5 alkyl, C2 to C5 alkenyl or C2 to C5 alkynyl group.
These novel piperazine derivatives of specific formula (I-a) are preferably 1,4-bis(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-2-(1xe2x80x2-piperidinocarbonyloxymethyl)piperazine, 1,4-bis(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-2-(1xe2x80x2-pyrrolidinocarbonyloxymethyl)piperazine, 1,4-bis(3xe2x80x2,4xe2x80x2-dimethoxybenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine, 1,4-bis(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-2-(isopropyloxycarbonylaminomethyl)piperazine, 1,4-bis(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-2-(tert-butylcarbonylaminomethyl)piperazine, 1-(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-4-(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxythiobenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine and 1,4-bis(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxythiobenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine.
According to another preferred embodiment of these novel piperazine derivatives, said derivatives correspond to the specific formula (I-b): 
in which R8 represents a hydrogen atom or a phenyl group, while R4, R5, R6, X and Y have the same meaning as in the general formula (I) defined above.
Advantageously, in these novel piperazine derivatives of specific formula (I-b), R4, R5 and R6 represent a methoxy group, X represents an O(Cxe2x95x90O) group, while Y represents a group NR9R10 in which R9 and R10 both represent a linear or branched C1 to C5 alkyl, C2 to C5 alkenyl or C2 to C5 alkynyl group, or alternatively a nitrogen heterocycle containing from 5 to 10 atoms and optionally one or more other heteroatoms chosen from nitrogen, oxygen and sulfur.
The novel piperazine derivatives corresponding to the specific formula (I-b) are preferably 1-benzyl-4-(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine and 1-diphenylmethyl-4-(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine.
According to yet another preferred embodiment of said novel piperazine derivatives, these derivatives correspond to the specific formula (I-c); 
in which R8 represents a hydrogen atom or a phenyl group, while R1, R2, R3, X and Y have the same meaning as in the general formula (I) defined above.
Advantageously, in the novel piperazine derivatives of specific formula (I-c), R1, R2 and R3 represent a methoxy group, X represents an O(Cxe2x95x90O) group, while Y represents a group NR9R10 in which R9and R10 both represent a linear or branched C1 to C5 alkyl, C2 to C5 alkenyl or C2 to C5 alkynyl group, or alternatively a nitrogen heterocycle containing from 5 to 10 atoms and optionally one or more other heteroatoms chosen from nitrogen, oxygen and sulfur.
Among these novel piperazine derivatives of specific formula (I-c), the one particularly preferred is 1-(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxybenzoyl)-4-benzyl-2-(N,N-diethylaminocarbonyloxymethyl)piperazine.
A subject of the present invention is also a novel piperazine derivative, which is 1-(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxythiobenzoyl)-4-(3xe2x80x2,4xe2x80x2,5xe2x80x2-trimethoxy-benzoyl)-2-(N,N-diethylaminocarbonyloxymethyl)piperazine, and the pharmaceutically acceptable salts thereof.
A subject of the present invention is also the novel piperazine derivatives as defined above, and the pharmaceutically acceptable salts thereof, for use as medicinal products.
A subject of the present invention is also pharmaceutical compositions, characterized in that they comprise as active principle at least one novel piperazine derivative as defined above, or a pharmaceutically acceptable salt thereof, and optionally excipients and additives taken from those conventionally used in pharmacy. Given the inhibitory properties shown by such a derivative, both on HIV replication and on the action of PAF, these pharmaceutical compositions especially find application in the prevention and/or treatment of HIV infection at all its stages: HIV-positive stage or Acquired Immunodeficiency Syndrome (AIDS) stage.